Microsomal Epoxide Hydrolase Gene Polymorphisms and Susceptibility to Prostate Cancer: a Mini Review

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Review Article Microsomal Epoxide Hydrolase Gene Polymorphisms and Susceptibility to Prostate Cancer: A Mini Review

Srivastava DS* and Dhaulakhandi DB Department of Biotechnology & Molecular Medicine, Pt. Abstract B.D. Sharma Post Graduate Institute of Medical Sciences, Microsomal Epoxide Hydrolase (MEH) is a crucial biotransformation enzyme India that has capability to metabolize a large number of structurally divergent, highly *Corresponding author: Daya Shankar Lal Srivastava, reactive epoxides, and numerous environmentally exposed carcinogens. It Department of Biotechnology and Molecular Medicine, catalyzes the conversion of xenobiotic epoxide compounds into more polar diol Pt. B.D. Sharma Post Graduate Institute of Medical metabolites and may play important part of the enzymatic defense against adverse Sciences, India effects of foreign compounds. Most commonly, two functional polymorphisms affecting MEH enzyme activity have been identified: one in exon 3 and other Received: June 08, 2015; Accepted: October 04, 2015; in exon 4 of the MEH gene, which results in his 113Tyr and Arg139 his amino Published: November 05, 2015 acid substitutions, respectively. Recent reports have shown that polymorphisms in MEH gene loci may be an important risk factor for susceptibility of prostate cancers, worldwide but inconsistent finding were also observed. To the best of our knowledge, globally there is no any comprehensive review has been published related to MEH gene polymorphisms and prostate cancer risk. Thus, in the current review, first time we have discussed the association between MEH gene polymorphisms, gene environmental interaction, and prostate cancer risk.

Keywords: Microsomal epoxide hydrolase; Prostate cancer; Carcinogens; Gene polymorphism; Gene-environmental interaction

Introduction addition of conjugates in reactive metabolites [20,22-23]. Therefore, persons with increased metabolic activity and decreased detoxifying Globally Prostate Cancer (PC) is the fourth most common cancer capacity of phase I and II enzymes may pose a higher risk for PC [24]. among men. PC incidence is highest among black men in the United States; however, low incidence has been reported in Asian countries MEH is a phase II enzyme that metabolizes a broad array of like China, Japan and India. Incidence of PC is low prior to age 50 epoxide substrates, Polycyclic Aromatic Hydrocarbons (PAHs), and increases exponentially till 80 years [1]. Development of PC has Benzo (a) Pyrenes (BaPs), butadiene, and pesticides into the less-toxic been a versatile phenomenon and numerous factors such as age, race, trans-dihydrodiol through trans-addition of water [14-16,20,21,25- dietary and life style, environmental, hormonal, family history and 27]. Previous studies have demonstrated that polymorphisms in genetic causes has been attributed for risk of prostate cancer [2-6]. MEH gene loci may be an important factor for genetic susceptibility of various cancers including the prostate [15,28-29], oral, pharynx, A study from Scandinavian countries- Sweden, Denmark, and and larynx [30], esophageal [31], and urinary bladder cancer [32]. Finland has shown that 40% of PC cases were attributed to inheritance, Although the underlying mechanisms related to prostate cancer and whereas the remainder most likely to be due to environmental CYP 450s as well as GSTs have been elucidated [18,22-23], but no factors [7]. The risk of prostate cancer among Asians increases when comprehensive review in relation to MEH gene polymorphism and they immigrate to North America and this strengthens the notion prostate cancer risk is available in the literature. Hence, in the present that environment factors play an important role in initiation and review we have summarized the recent advances of MEH gene progression of PC [8]. Previous studies have shown that increased total polymorphisms for the susceptibility of prostate cancer in relation to fat intake, animal fat intake, and consumption of red meat, cigarette metabolizing of environmental carcinogens. smoking, and exposure of various carcinogens from petroleum related industries such as polycyclic aromatic hydrocarbon, and Microsomal Epoxide Hydrolase(MEH) heterocyclic aromatic amine [2-amino-1-methyl-6-phenylimidazo Localization: Microsomal Epoxide Hydrolase (MEH) is a [4, 5-b] pyridine] play significant role in prostate cancer susceptibility smooth endoplasmic reticulum enzyme, expressed in large variety of in different ethnicities [9-16]. cell types such as microsome, endoplasmic reticulum, and integral to membrane. However, MEH expression is usually higher in liver and The enzymes of the Cytochrome P450 family (phase I enzymes) other metabolizing organs such as testis, adrenal gland, lung, kidney, play important role in the activation of exogenous and/ or endogenous brain, prostate, heart and an epithelial cell which suggests that MEH carcinogens to more reactive metabolites that may react with DNA may ensure widespread defense against potential genotoxic epoxides and cause mutations [17- 21]. However, phase II enzymes, such as the [17,33-38]. Glutathione S-Transferases (GSTs), N-Acetyl Transferases (NATs), Microsomal Epoxide Hydrolase (MEH), and sulfotransferases are Classification: Five classes of mammalian epoxide hydrolase generally involved in detoxification of chemical carcinogens by have been characterized, which are immunologically and structurally

Austin J Urol - Volume 2 Issue 3 - 2015 Citation: Srivastava DS and Dhaulakhandi DB. Microsomal Epoxide Hydrolase Gene Polymorphisms and ISSN: 2472-3606 | www.austinpublishinggroup.com Susceptibility to Prostate Cancer: A Mini Review. Austin J Urol. 2015; 2(3): 1030. Srivastava et al. © All rights are reserved Srivastava DS Austin Publishing Group distinct in nature [17,39]. These are: cytosolic hepoxilin A3 hydrolase Published reports in different ethnic groups have shown that the [40], microsomal enzyme associated with specific substrate such as frequencies of the His allele at exon 3 were in range of 40.0–56.2% cholesterol 5,6-oxide [41]; leukotriene A4 hydrolase [42], soluble among Asians; 30.6–37.0% among whites, and 12.7–26.0% in blacks epoxide hydrolase [43], and microsomal epoxide hydrolase [44]. population, worldwide. However, frequency distribution of the Arg Soluble (SEH) and Microsomal Epoxide Hydrolases (MEH) may allele at exon 4 among Asians, whites, and blacks were in range of 11.3– play an important role in the metabolism of xenobiotic compounds. 16.3%, 17.5–19.8%, and 24.0–30.3%, respectively [38,63,64]. Recently The soluble form of epoxide hydrolase participate in metabolizing data from few studies addressing a possible association between MEH trans-substituted epoxides [45], however, other forms of epoxide gene polymorphisms and cancer suggests a dual role for the MEH hydrolase metabolise cis-confguration of arene, alkene, aliphatic in the carcinogenic process. It has been reported that MEH His113 epoxides, epoxides of steroids, arachidonic acid derivatives [46-47] variant allele increases the risk of various cancers i.e. esophageal [31], and leukotrienes [48-49]. colorectal [58], bladder [32] and prostate [29], but decreases the risk Structure: MEH gene is also known as EPHX1, EPHX, and of lung cancer [65] whereas; MEH His139 variant allele increases the EPOX or faklor. This gene is present on long arm of the chromosome risk of oral, pharynx, and larynx cancer [30]. However, no association 1 (1q42.1.8) and consists of 8 introns and 9 exons, of which exons 2 could be established between MEH gene polymorphism and bladder to 9 are the coding exons [17,50-51]. Mammalian EPHX1 is a 51kDa cancer susceptibility in German population [66]. protein having 455amino acid residue; attached to cytosolic site of MEH Gene polymorphisms and Prostate cancer risk endoplasmic reticulum membrane by a single N terminal anchor [52]. Etiology of prostate cancer remains unclear because prostate Further, the anchor is connected to generic alfa/beta hydrolase fold carcinogenesis is a complex process involving both genetic as well as by the 100 amino acid residues stretch [17,53]. Quaternary structure environmental factors [2-8,11]. Recent data has shown that cigarette of mammalian EPHX1 is not known but its association with CYP and smoking is associated with the susceptibility of prostate cancer in CYP reductase to a multienzyme complex [54] cannot be ruled out. various studies [3-5,11,14-15, 20, 29,67] but inconsistent finding Functions: Microsomal epoxide hydrolase enzyme is a were also reported [68]. In environmental carcinogens metabolism, protective enzyme involved in oxidative defense against a number of exposed carcinogens first require metabolic activation, evasion of environmental substances [6]. In detoxification process, it catalyzes detoxification, thereafter binding of activated carcinogens toDNA hydrolysis of lipophilic substituted epoxides of cis-confguration of forming DNA adducts that are accountable for mutation during arenes, alkenes, and aliphatic epoxides from the polycyclic aromatic replication process and finally resulting into prostate cancer (Figure hydrocarbons and aromatic amines to trans-dihydrodiols [17,33,55]. 1). However, in some cases [benzo(a)pyrene present in tobacco smoke], It is well known that tobacco contain 1015-1017 free radicals highly reactive carcinogenic compounds (benzo(a)pyrene 7,8- diol-9,10 epoxide) are also generated [56]. Thus, MEH plays an important role in both the metabolic activation and detoxification of environmentally exposed carcinogens. MEH gene polymorphisms The MEH protein and nucleic acid sequences are highly conserved, and appear universally expressed [57]. Earlier published data has shown that alteration in the coding region may appear to influence activity of MEH enzyme through the alteration of protein stability rather than enzyme kinetics [49,58-59]. Broad inter- individual variability in the enzymatic activity of MEH has been attributed in part to two identified polymorphisms. Most commonly, two functional polymorphisms have been identified within exon 3 and 4 of the MEH gene, which results in his113Tyr and Arg139 his amino acid substitutions, respectively [57,59]. In vitro expression analyses pointed that the corresponding MEH activities decrease approximately 40% due to point mutation in exon 3 (Tyr113); Figure 1: In normal process, exposed carcinogens may require metabolic however, the amino acid substitution (histamine to argentine) activation by the phase I enzymes (CYP450s) and forming less polar and induced by point mutation in exon 4 (His139) increases MEH activity more toxic activated intermediates. Phase I enzymes metabolized products now act as substrates for the Phase II enzymes which catalyzes the by 25% [59]. On the basis of presence or absence of the exon 3 and conjugation of glutathione, acetyl acetyl coenzyme or epoxide hydroxyl group exon 4, polymorphism of MEH gene, MEH activity was classified into in activated carcinogens through the glutathione S-transferases, N-acetyl low, intermediate, and high imputed phenotype [60-61]. It was based transfer eases, or microsomal ehoxide hydrolase and produce readily on the assumption that the Tyr allele at exon 3 and the His allele at extractable less toxic, more polar hydrophilic compounds that may excreted out from the body through the bile or urine. However, in stress condition exon 4 confer normal activity whereas the His allele at exon 3 confers when exposed carcinogens are not metabolized properly may results more low activity; however, the high activity were conferred by the Arg active intermediates and undergoes in evasion of detoxification. These active allele at exon 4. Beside the coding region, several other non-coding intermediates now binds to DNA forming DNA adducts that are accountable polymorphisms were also elucidated, which may possibly affect for mutation during replication process and ultimately resulting into prostate cancer. transcriptional regulation of the MEH gene [62].

Submit your Manuscript | www.austinpublishinggroup.com Austin J Urol 2(3): id1030 (2015) - Page - 02 Srivastava DS Austin Publishing Group and other highly reactive electrophiles such as polycyclic aromatic Recently, a case control study conducted in American population hydrocarbons, heterocyclic amines and naphthalene and epoxide (in 439 men with PC and 479 unaffected brothers as a control) derivatives. These compounds are accountable for electrophonic showed non-significant association either in MEH gene alone or in reactions which may target critical biological molecules such as combination with smokers for prostate cancer risk in either total DNA, lipids and proteins, which ultimately lead to mutagenic, toxic, study population or in Caucasians alone [64]. In this study only 413 and carcinogenic effects [11,37,54]. Tobacco associated carcinogens families participated out of which 90% were Caucasian, 9% African- including PAHs (Polycyclic Aromatic Hydrocarbons) are known to American, and rest 1% Asian. Later on by the same group, potential induce MEH activity [6]. Studies in mice model also indicated that association between smoking and MEH gene polymorphism with endogenous and exogenous carcinogen compounds (cooked food PAH-DNA adducts levels in tumor and adjacent non-tumor prostate derivative and tobacco containing heterocyclic amine), 2-amino-1- cells was evaluated using immune histochemical assay in 400 men methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP), when fed to rats with prostate cancer, out of them 52.2% was Caucasians and rest cause prostate cancer [12-13]. Previously published data has shown were African-Americans. These authors observed non significant that MEH enzyme play an important role in detoxification of tobacco association either with ever or current smoking or any of the PAH and other environmental carcinogens induced oxidative substances metabolizing gene polymorphisms with PAH-DNA adduct levels in such as PAH, benzo (a) pyrene-derived benzo (a) pyrene 7, 8-epoxide, the total sample [20]. However stratification by race, revealed that and PHIP, epoxides of steroids, pesticides, and derivatives of arenes, Caucasian ever smokers had significantly higher PAH-DNA adducts alkenes, and aliphatic epoxides [14]. Thus, MEH plays a dual role due levels than non-smokers in tumor cells (0.1748 ± 0.0052 versus 0.1507 to its ability of both, activation and detoxification of carcinogenic ± 0.0070; P = 0.006). Moreover, Caucasians carrying two copies of the substances. Consequently, increased activity of MEH may be MEH 139Arg allele had significantly decreased PAH-DNA adduct responsible for cancer protection due to increased detoxification of levels in both, tumor and non-tumor cells. exposed carcinogens in the body or enhances the risk due to activation While studying the association between smoking and MEH gene of specific carcinogens. Globally, several studies have shown relation on PAH-DNA adduct levels, authors observed increased DNA adducts of polymorphisms of exon 3 (His113Tyr) and exon 4 (Arg139His) of in tumor cells of PC patients of Caucasian ever smokers carrying MEH gene with prostate cancer risk. These studies are narrated in the the potentially faster genotypes of MEH (139His/His or His/Arg) following text. compared with non-smokers with the MEH 139Arg/Arg genotype. Association between MEH gene polymorphism (exon 3) and Furthermore, in combined effects between ethnicity, smoking, and prostate cancer was first studied by the Figer et al. (2003) in Israeli MEH genotypes; authors observed significant interaction between Jewish population. These authors detected significant higher ethnicity and in ever smoking [interaction P value = 0.02], and frequency of His113 allele (21.4%:33/154) (P< 0.001) in individuals ethnicity and the MEH His139 genotypes (Arg/Arg versus His/His aged above 61 years, compared with 5.7% (4/70) in earlier onset or His/Arg; P value = 0.02) in tumor cells of African Americans as disease [28]. Moreover, within the group of late-onset disease, the compared to Caucasians group [20]. His113 allele of exon 3 of MEH gene illustrated significantly higher Recently an agricultural health study in American population frequency in grade II tumor (18%: 34/188) as compared to grade I [15] carried out by Kuotros et al., (2011) investigated the role of the tumor (5.5%: 2/36). interaction between pesticides and polymorphisms in xenobiotic Mittal and Srivastava, (2007) in a study comprising of 130 PC metabolizing enzymes, and susceptibility to prostate cancer in 2,220 patients and 140 controls in north Indian population, observed participants. These authors demonstrated significant association significant association with exon 3 Tyr/His (OR=2.66, p=0.001) and with polymorphisms in exon 3 and exon 4 of MEH gene for prostate His/His genotypes of MEH gene (OR=4.90, p< 0.001) for PC risk; cancer risk [rs2740168 (p-trend=0.0042) and rs2292566, ORper allele whereas, no association could be established with exon 4 genotypes = 1.27 (95% CI: 1.07, 1.51)]. Furthermore the study suggested that of the MEH gene [29]. However, in gene environment interaction, men carrying the variant allele for MEH gene g(rs17309872) have significant associations between tobacco users with heterozygous higher prostate cancer risk with high pesticides exposed group in and homozygous variant genotype of exon 3 (OR=4.90, p<0.000) and comparison to non- exposed group (OR=2.1, p-interaction=0.01). His genotype for the exon 4 of MEH gene (p=0.003) was observed. A study by Sivonova et al. (2012) investigated microsomal epoxide Similarly, in haplotype analysis, significant association was detected hydrolase gene polymorphisms with prostate cancer risk in Slovak for His113/ His139 haplotype of MEH (OR=2.48; p=0.002) as population in 194 histologically confirmed prostate cancer patients compared to the non risk haplotype (normal phenotype of MEH) and 305 normal healthy individuals. This study has demonstrated for PC susceptibility. Further analysis of combined genotypes/ moderate association with the His/Arg and Arg/Arg genotypes at phenotypes of MEH, PC group pointed significantly higher risk for exon 4 of MEH gene; however no association was found between predicted ‘slow’, and ‘very slow’ phenotype of MEH gene, respectively exon 3 of MEH gene with prostate cancer risk. Moreover, significant as compared to normal phenotype [29]. Thus, synergistic interaction associations were observed between normal phenotype and smoking; between the slow genotypes of MEH and tobacco users found implies while among non-smokers, increased risk was indicated for rapid that in the tobacco users, detoxification of carcinogenic compound phenotype when compared with normal phenotype of non-smokers decreases, and eventually results in an increased risk for prostate 0. Furthermore, authors showed that smokers were at increased risk cancer. It suggests that persons having His allele of exon 3 and exon if they have His/Arg genotypes of exon 4 as compared with slow 4 of MEH gene undergo decreased detoxification of carcinogenic genotype (His/His) of non-smokers. compounds due to altered form of enzyme.

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A multiethnic, population-based case–control study by Joshi would help to identify drug-induced diseases, and to provide et al. (2012) in American population (1096 controls, 717 localized appropriate dosages of drugs to individuals based on their genotype. and 1140 advanced PC cases); have examined association between The results highlight the difficulties encountered in estimating risk nutrient density-adjusted intake of red meat and poultry with exon by studying a single locus polymorphism. It also suggests that there 3 and exon 4 of MEH gene polymorphisms for prostate cancer risk. is functional synergy between several xenobiotic-metabolizing These authors have observed non-significant association either MEH enzymes, especially between CYP isoforms, GSTP1, GSTT1, NAT1, gene polymorphisms alone or in combination with nutrient density- NAT2, MEH and sulfotransferases as suggested in other association adjusted intake of red meat and poultry for PC susceptibility [68]. studies of cancer susceptibility. Nevertheless, we cannot exclude the possibility that these enzymes are also involved in the metabolism Recently a study in American population by Catsburg et al. (2012) of critical endogenous molecules, thereby playing a role in cell in 497 localized and 936 advanced PC cases and 760 controls have proliferation and differentiation. Further study in relation to the established increased risk for localized PC as compared to controls evolution of races and disease prevalence may help to identify the with His/His genotypes of exon 3 of MEH gene ( OR= 1.91; 95% CI contributions of polymorphism in alleged susceptibility to diseases, = 1.14–3.15). However, a test of heterogeneity for the difference of apart from delineating its contributions to ethnic differences in associations between advanced and localized disease non significant the pharmacology of drugs metabolized by CYP isoforms, GSTs, association was observed [69]. Thus, the positive association between NAT1, NAT2, MEH and sulfotransferases for testing possible gene- the His allele and localized PC may suggests that the slow allele environment interactions in prostate cancer. The potential value (His allele) may contribute toward increased metabolic activation, of the genetic polymorphism of drug metabolizing enzymes can possibly by reducing the bioavailability of substrates for PAH epoxide help to understand the basic biological process of cancer initiation detoxification. and assessing its value as a marker for tumor development so that Conclusion and Future Prospective the utility and implication of the concept of genetic polymorphism of drug metabolizing enzymes can be assessed in prostate cancer Xenobiotic metabolizing microsomal epoxide hydrolase is management. a phase II polymorphic gene encoding enzyme that metabolizes environmental and tobacco carcinogen to less active and more References soluble dihydrodiols, through the trans addition of water [12,34- 1. Sinha R, Anderson DE, McDonald SS, Greenwald P. Cancer risk and diet in 35,54]. The epoxide hydrolase acts coordinatedly with CYP1A1 and India. J Postgrad Med. 2003; 49: 222-228. 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